This present invention relates to methods to treat and prevent damage to mucosal tissue.
Mucous membranes (or mucosa) typically possess an epithelial layer beneath which is a lamina propria rich in seromucous glands and a dense network of small blood vessels. (Ohkubo et al., Am. J. Respir. Cell Mol. Biol. 11:173-180 1994).
The present invention provides methods, pharmaceutical compositions, and kits for treating and preventing damage to mucosal tissue, comprising administering to a subject in need thereof an amount effective to treat or prevent damage to mucosal tissue of at least one active agent of the invention. The mucosal tissue to be treated is preferably selected from oral, buccal, sublingual, nasal, vaginal, rectal, aural, lung, and gastrointestinal mucosa. Examples of damage to mucosal tissue are provided below.
Mucosal ulcers of the mouth, commonly referred to as aphthous stomatitis, aphthous ulcers, or canker sores often appear on the unkeratinized oral mucosal surface of the soft palate, the ventral or lateral tongue, the buccal-labial mucosa, or the floor of the mouth. (U.S. Pat. No. 5,981,499, herein incorporated by reference in its entirety.) Small aphthous ulcers usually heat spontaneously in one to three weeks, but larger ulcers may require months to resolve, often with scarring.
Aphthous-like ulcers can be associated with allergic reactions, human immunodeficiency virus and herpes simplex virus infection, menstrual cycles, prolonged fever, emotional stress, local trauma, low serum iron, ferritin or zinc levels, deficiency of vitamin B12, malabsorption in association with celiac or Crohn""s disease, food hypersensitivity, and drug reactions.
The first stage of an emerging canker is a vesicle in the stratum granulosum of the mucosal squamous epithelium, produced by intraepithelial edema. (U.S. Pat. No. 5,981,499) The painful symptoms of the ulcer do not occur until the vesicle breaks, presenting an area of ulceration which disrupts the normal epithelium of the mucosa. Once an ulcer forms, the mucosa is no longer protected by an intact epithelium and the raw surface of the ulcer is exposed to the microorganisms that normally inhabit the oral cavity.
Examples of indigenous oral flora include lactobacilli, actinomyces, leptotrichiae, xcex1-hemolytic streptococci, enterococci, gram-positive cocci, Neisseriae, diphtheroid bacilli, fusiform bacilli, bacteroides, spirochetes, yeasts and Candida. (U.S. Pat. No. 5,981,499) When existent in normally balanced proportions, these microorganisms do not usually produce disease in the intact oral mucosa of a healthy person. However, upon rupture of a canker ulcer, opportunistic pathogens quickly destroy the remnants of the local surface barrier of the oral mucosa. The result is a secondary infection, characterized by a dense acute and a chronic inflammatory cell infiltration of the exposed connective tissue of the lamina propria mucosae at the crater of the ulcer.
Despite the multifactorial etiology of aphthous ulcers, secondary infections arise after rupture of the intraepithelial vesicle during the early development of all cankers. Control of infection is essential for promoting the healing process. (U.S. Pat. No. 5,981,499)
The treatment of aphthous stomatitis to date has been palliative, using various measures to lessen the pain, to control secondary infection, and to reduce inflammatory reaction after the painful ulcer is established. The treatments of choice for aphthous ulcers have varied over the years, but in general, palliative treatments have met with only limited success.
In another example, leukoplakia is a localized irritation of the buccal mucosa due to direct contact of smoked or smokeless tobacco. (U.S. Pat. No. 5,906,811; incorporated by reference herein in its entirety.) Although leukoplakia is a benign oral lesion, it has a malignant potential, requiring a biopsy of the lesion to rule out cancer. Leukoplakia may regress or resolve completely when use of tobacco products is discontinued.
Other examples of damage to mucosal tissue include oral mucositis, burning mouth syndrome, lichen planus, denture sores, gingivitus, recent oral surgical sites, cervical dysplasia, vulva leukoplakia and other vulval lesions, Bechets Syndrome, radiotherapy induced mucositis, post-operative gum pain, traumatic mouth lesions, post-radiotherapy vaginitis, non-specific vaginal inflammatory conditions, other viral auto-immune and inflammatory ulcerations of the mucosa, nonspecific ulcer of colon, ulcerative colitis induced by nonspecific inflammations, and Crohn""s disease. (See U.S. Pat. Nos. 5,972,906 and 5,576,331, both references incorporated by reference herein in their entirety.)
Thus, methods to prevent and/or treat damage to mucosal tissue would be of great utility.
The present invention provides methods and kits for treating or preventing damage to mucosal tissue by contacting the mucosal tissue with an amount effective to treat or prevent damage to mucosal tissue of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AII), AII analogues, AII fragments or analogues thereof, or AII AT2 type 2 receptor agonists, either alone, combined, or in further combination with other mucosal-protecting compounds, including anti-inflammatory drugs, angiotensin converting enzyme (ACE) inhibitors, anti-infectives growth factors, and antihistamines.